The stability of FKBP9 maintained by BiP is crucial for glioma progression  

作　　者：Shirong Li Wangxiao Xia Bin Sun Weiyan Peng Dong Yang Jing Gao Shuai He Hua Yang Yongjie Zhu Hu Zhou Tingxiu Xiang Qingpeng Kong Xudong Zhao 

机构地区：[1]Division of Abdominal Tumor Multimodality Treatment and Laboratory of Animal Tumor Models,Cancer Center and State Key Laboratory of Respiratory Health and Multimorbidity and Frontiers Science Center for Disease-related Molecular Network,West China Hospital,Sichuan University,Chengdu,Sichuan 610041,China [2]State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming,Yunnan 650223,China [3]Key Laboratory of Molecular Oncology and Epigenetics,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,China [4]Department of Analyticali Chemistry and CAS Key Laboratory of Receptor Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [5]The Third People's Hospital of Yunnan Province,Kunming,Yunnan 650600,China

出　　处：《Genes & Diseases》2024年第6期441-451,共11页基因与疾病（英文）

基　　金：supported by the National Natural Science Foundation of China (No.82103107 to B.S.);the open project from the State Key Laboratory of Genetic Resources and Evolution of China (No.GREKF19-06 to H.Y.);the 1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University (No.ZYYC20002 to X.D.Z.).

摘　　要：FK506-binding protein 9(FKBP9)is involved in tumor malignancy by resistance to endoplasmic reticulum(ER)stress,and the up-regulation of FKBP9 is associated with patients'poor prognosis.The current knowledge of the molecular mechanisms is still limited.One pre-vious study showed that FKBP9 could confer glioblastoma cell resistance to ER stress through ASK1-p38 signaling.However,the upstream regulatory mechanism of FKBP9 expression is still indistinct.In this study,we identified the FKBP9 binding proteins using co-immunoprecipitation followed by mass spectrometry.Results showed that FKBP9 interacted with the binding immu-noglobulin protein(BiP).BiP bound directly to FKBP9 with high affinity.BiP prolonged the half-life of the FKBP9 protein and stabilized the FKBP9 protein.BiP and FKBP9 protein levels were positively correlated in patients with glioma,and patients with high expression of BiP and FKBP9 showed a worse prognosis.Further studies showed that FKBP9 knockout in genetically engineered mice inhibited intracranial glioblastoma formation and prolonged survival by decreasing cellular proliferation and ER stress-induced CHOP-related apoptosis.Moreover,normal cells may depend less on FKBP9,as shown by the absence of apoptosis upon FKBP9 knockdown in a non-transformed human cell line and overall normal development in homozygous knockout mice.These findings suggest an important role of BiP-regulated FKBP9-associated signaling in glioma progression and the BiP-FKBP9 axis may be a potential therapeutic target forglioma.

关 键 词：BIP Endoplasmic reticulum stress FKBP9 GLIOMA Knockout mice 

分 类 号：R739.41[医药卫生—肿瘤]